Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers

Most local anaesthetics used clinically are relatively hydrophobic molecules that gain access to their blocking site on the sodium channel by diffusing into or through the cell membrane. These anaesthetics block sodium channels and thereby the excitability of all neurons, not just sensory neurons. We tested the possibility of selectively blocking the excitability of primary sensory nociceptor (pain-sensing) neurons by introducing the charged, membrane-impermeant lidocaine derivative QX-314 through the pore of the noxious-heat-sensitive TRPV1 channel. Here we show that charged sodium-channel blockers can be targeted into nociceptors by the application of TRPV1 agonists to produce a pain-specific local anaesthesia. QX-314 applied externally had no effect on the activity of sodium channels in small sensory neurons when applied alone, but when applied in the presence of the TRPV1 agonist capsaicin, QX-314 blocked sodium channels and inhibited excitability. Inhibition by co-applied QX-314 and capsaicin was restricted to neurons expressing TRPV1. Injection of QX-314 together with capsaicin into rat hindpaws produced a long-lasting (more than 2 h) increase in mechanical and thermal nociceptive thresholds. Long-lasting decreases in pain sensitivity were also seen with regional injection of QX-314 and capsaicin near the sciatic nerve; however, in contrast to the effect of lidocaine, the application of QX-314 and capsaicin together was not accompanied by motor or tactile deficits.

[1]  B. Hille,et al.  Local anesthetics: hydrophilic and hydrophobic pathways for the drug- receptor reaction , 1977, The Journal of general physiology.

[2]  D. Frazier,et al.  The site of action and active form of local anesthetics. II. Experiments with quaternary compounds. , 1970, Journal of Pharmacology and Experimental Therapeutics.

[3]  W. Willis,et al.  The effects of G-protein and protein kinase inhibitors on the behavioral responses of rats to intradermal injection of capsaicin , 1997, Pain.

[4]  R. Dubner,et al.  A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia , 1987, Pain.

[5]  I. Chessell,et al.  The Voltage-Gated Sodium Channel Nav1.9 Is an Effector of Peripheral Inflammatory Pain Hypersensitivity , 2006, The Journal of Neuroscience.

[6]  G. Strichartz,et al.  The Inhibition of Sodium Currents in Myelinated Nerve by Quaternary Derivatives of Lidocaine , 1973, The Journal of general physiology.

[7]  Bernd Nilius,et al.  Permeation and selectivity of TRP channels. , 2006, Annual review of physiology.

[8]  W. Catterall,et al.  Molecular determinants of drug access to the receptor site for antiarrhythmic drugs in the cardiac Na+ channel. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[9]  K. Hara,et al.  The Interaction Between Gamma-Aminobutyric Acid Agonists and Diltiazem in Visceral Antinociception in Rats , 2004, Anesthesia and analgesia.

[10]  W. Almers,et al.  Interactions between quaternary lidocaine, the sodium channel gates, and tetrodotoxin. , 1979, Biophysical journal.

[11]  D. Julius,et al.  The vanilloid receptor: a molecular gateway to the pain pathway. , 2001, Annual review of neuroscience.

[12]  H. Fozzard,et al.  A critical residue for isoform difference in tetrodotoxin affinity is a molecular determinant of the external access path for local anesthetics in the cardiac sodium channel. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[13]  J. Yeh Sodium inactivation mechanism modulates QX-314 block of sodium channels in squid axons. , 1978, Biophysical journal.

[14]  G. Schultz,et al.  TRPV1 Acts as Proton Channel to Induce Acidification in Nociceptive Neurons* , 2004, Journal of Biological Chemistry.

[15]  S. Simon,et al.  Capsaicin inhibits activation of voltage-gated sodium currents in capsaicin-sensitive trigeminal ganglion neurons. , 2001, Journal of neurophysiology.

[16]  D. Frazier,et al.  Site of action and active form of local anesthetics. , 1971, Neurosciences research.

[17]  J. T. Corwin,et al.  Lighting up the Senses: FM1-43 Loading of Sensory Cells through Nonselective Ion Channels , 2003, The Journal of Neuroscience.